Combining structure-based and 3D QSAR pharmacophore models to discover diverse ligands against EGFR in oral cancer

Background: Epidermal growth factor receptor-tyrosine kinase (EGFR-TK) is a well-known hallmark of oral and oropharyngeal cancers, as its overexpression leads to poor prognosis and malignancy. The activating EGFR mutations (particularly T790M and L858R double mutant) are a major challenge causing drug resistance, especially in the treatment of oral cancers. Methodology: This paper is an effort to exploit both structure-based and ligand-based pharmacophore modeling to discover EGFR-TK inhibitors, which show inhibition of proliferation of erlotinib-resistant FaDu and Cal27 oral cancer cells. Interestingly, the hit compound H2 also showed an effect on the downstream glucose and lactate metabolism pathways. Conclusion: The results indicate the potential of H2 to be developed as an EGFR-based metabolic inhibitor for oral cancer treatment.